CEACAM1: A link between metabolic and cardiovascular diseases

CEACAM1：代谢与心血管疾病之间的联系

• 批准号: 8597957
• 负责人: Sonia M. Najjar
• 金额: $ 36.79万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8597957
• 关键词: Ablation; Address; Adipose tissue; Animal Model; Apolipoprotein E; Apolipoproteins B; Arterial Fatty Streak; Atherosclerosis; Automobile Driving; Blood; Blood Vessels; Cardiovascular Diseases; Cattle; Cause of Death; Cell physiology; Cells; Central obesity; Cholesterol; Clinical Research; Data; Development; Diet; Disease; Dyslipidemias; Endothelial Cells; Exhibits; Experimental Models; Eye; Fatty Acids; Functional disorder; Genes; Hepatic; Hepatocyte; Hyperinsulinism; Hyperlipidemia; Incidence; Indium; Individual; Insulin; Insulin Receptor; Insulin Resistance; Intervention; Knockout Mice; LDL Cholesterol Lipoproteins; Link; Lipids; Liver; Low Density Lipoprotein Receptor; Mediating; Membrane; Metabolic Diseases; Metabolic syndrome; Metabolism; Modeling; Mus; Pathogenesis; Pathway interactions; Patients; Phenotype; Phosphorylation; Plasma; Play; Predisposition; Production; Regulation; Reporting; Role; Serum; Signal Transduction; Site; Skeletal Muscle; Testing; Therapeutic; Toxic effect; Triglycerides; United States; Vascular Diseases; Vascular Endothelial Cell; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factors; Vascular Permeabilities; Vasodilation; Very low density lipoprotein; Work; atherogenesis; base; carcinoembryonic antigen-related cell adhesion molecules; cell type; endothelial dysfunction; feeding; gain of function; high risk; human NOS3 protein; in vivo; innovation; insulin sensitivity; insulin signaling; lipid biosynthesis; loss of function; mouse model; prevent; response

Individuals with metabolic diseases are at a higher risk of developing atherosclerosis, a leading cause of death in the United States and worldwide. Earlier studies have linked dyslipidemia to the initiation and progression of atherosclerosis. However, recent clinical studies raised concerns about the efficacy of lowering plasma cholesterol levels in the progression of atherosclerosis. Although insulin resistance is associated with increased incidence of cardiovascular disease, whether it leads to atherosclerosis independently of its accompanying dyslipidemia remains unclear, largely because of the lack of a suitable animal model to address this question. The CarcinoEmbryonic Antigen-related Cell Adhesion Molecule-1 (CEACAM1) regulates insulin sensitivity by promoting insulin clearance in liver. Accordingly, global null deletion of Ceacam1 gene impairs hepatic insulin clearance and causes hyperinsulinemia, which in turn, results in systemic insulin resistance. Preliminary data show: (i) that global Cc1-/- null mice develop early atherosclerotic lesions and vascular dysfunction even under normal feeding conditions, and (ii) that this occurs in the absence of hyperlipidemia, despite VLDL/LDL cholesterol levels that are usually associated with atherosclerosis regression, not development. This unique animal model of atherogenesis with isolated insulin resistance in the absence of hyperlipidemia demonstrates that systemic insulin resistance resulting from hyperinsulinemia leads to vascular dysfunction and atherosclerosis in the absence of hyperlipidemia. Because phosphorylation of CEACAM1 by both insulin and VEGF receptors regulates Akt1 activation of endothelial Nitric Oxide Synthase (eNOS), an essential step in mediating endothelial function, it is reasonable to propose that CEACAM1 is the shared downstream element in VEGF and insulin signaling in endothelial cells, whose inactivation impinges upon both pathways and causes endothelial dysfunction in insulin resistance. To test this hypothesis, the regulatory effect of CEACAM1 on insulin action along the liver/endothelial cell axis will be investigated. Aim 1 examines whether hyperinsulinemia caused by impaired hepatic insulin clearance, alters insulin action in the endothelial cell, and in this cell-nonautonomous fashion, initiates atheroma development. Aim 2 examines whether altered signaling through CEACAM1-dependent pathways disrupts the endothelial cell's response to insulin and VEGF, and in this cell-autonomous fashion, drives endothelial dysfunction and initiates atherosclerosis. To investigate the specific role of hepatic and endothelial cell CEACAM1 in the pathogenesis of atherosclerosis and vascular dysfunction, a newly generated set of unique animal models of loss-of-function and gain-of-function will be used. Answering these questions will delineate new CEACAM1-dependent mechanisms underlying atherosclerosis along the liver/endothelial cell axis, and pinpoint sites of pharmacologic intervention.

患有代谢疾病的人患动脉粥样硬化的风险更高，这是 在美国和全球死亡。较早的研究已将血脂异常与开始和 动脉粥样硬化的进展。但是，最近的临床研究引起了人们对 在动脉粥样硬化进展中降低血浆胆固醇水平。虽然胰岛素抵抗是 与心血管疾病的发病率增加有关，是否导致动脉粥样硬化 独立于伴随的血脂异常仍然不清楚，这主要是因为缺乏 合适的动物模型来解决这个问题。与癌脑抗原相关的细胞粘附 分子1（CEACAM1）通过促进肝脏中的胰岛素清除来调节胰岛素敏感性。因此， CEACAM1基因的全球无效缺失会损害肝胰岛素清除率并引起高胰岛素血症， 反过来，导致全身性胰岛素抵抗。初步数据显示：（i）全局cc1 - / - null 小鼠即使在正常喂养下也会出现早期的动脉粥样硬化病变和血管功能障碍 条件，（ii）尽管VLDL/LDL胆固醇，但在没有高脂血症的情况下发生这种情况 通常与动脉粥样硬化回归相关的水平，而不是发育。这种独特的动物 在没有高脂血症的情况下，具有分离的胰岛素耐药性动脉粥样硬化模型证明 高胰岛素血症引起的全身性胰岛素抵抗会导致血管功能障碍和 在没有高脂血症的情况下，动脉粥样硬化。因为两种胰岛素对CeCAM1的磷酸化 VEGF受体调节内皮一氧化氮合酶（ENOS）的AKT1激活，这是必不可少的 介导内皮功能的一步，合理地提出CECAM1是共享 内皮细胞中VEGF和胰岛素信号传导的下游元素，其失活 在胰岛素抵抗中构成途径并引起内皮功能障碍。测试 该假设，CEACAM1对沿肝脏/内皮细胞轴胰岛素作用的调节作用 将被调查。 AIM 1检查是否由肝胰岛素受损引起的高胰岛素血症是否引起 清除，改变内皮细胞中的胰岛素作用，并以这种细胞的态度方式启动 动脉瘤发展。 AIM 2检查是否通过CEACAM1依赖性改变了信号传导 途径破坏了内皮细胞对胰岛素和VEGF的反应，在此细胞自动中 时尚，驱动内皮功能障碍并引发动脉粥样硬化。调查特定作用 在动脉粥样硬化和血管功能障碍的发病机理中，肝和内皮细胞CEACAM1， 将使用新生成的一组独特的功能丧失和功能获得的动物模型。 回答这些问题将描述依赖于CEACAM1的新机制 沿着肝脏/内皮细胞轴的动脉粥样硬化，并确定了药理学干预的位点。